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(Circulation. 2005;112:553-562.)
© 2005 American Heart Association, Inc.

Hypertension

Increased Susceptibility to Pulmonary Hypertension in Heterozygous BMPR2-Mutant Mice

Yanli Song, MD, PhD; John E. Jones, MD; Hideyuki Beppu, MD, PhD; John F. Keaney, Jr, MD; Joseph Loscalzo, MD, PhD; Ying-Yi Zhang, PhD

From the Whitaker Cardiovascular Institute and Evans Department of Medicine (Y.S., J.E.J., J.F.K., J.L., Y.-Y.Z.), Boston University School of Medicine, Boston, and the Cardiovascular Research Center (H.B.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass. Drs Song, Loscalzo, and Zhang are currently affiliated with the Cardiovascular Research Laboratory; Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Ying-Yi Zhang, PhD, Cardiovascular Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 0630, Boston, MA 02115. E-mail yyzhang{at}rics.bwh.harvard.edu

Received July 14, 2004; revision received January 26, 2005; accepted February 4, 2005.

Background— Bone morphogenetic protein receptor-2 (BMPR2)–heterozygous, mutant (BMPR2^+/–) mice have a genetic trait similar to that of certain patients with idiopathic pulmonary arterial hypertension (IPAH). To understand the role of BMPR2 in the development of IPAH, we examined the phenotype of BMPR2^+/– mice and their response to inflammatory stress.

Methods and Results— BMPR2^+/– mice were found to have the same life span, right ventricular systolic pressure (RVSP), and lung histology as those of wild-type mice under unstressed conditions. However, when treated with recombinant adenovirus expressing 5-lipoxygenase (Ad5LO), BMPR2^+/– mice exhibited significantly higher RVSP than wild-type mice. The increase of RVSP occurred in the first 2 weeks after Ad5LO delivery. Modest but significant muscularization of distal pulmonary arterioles appeared in BMPR2^+/– mice 4 weeks after Ad5LO treatment. Measurement of urinary metabolites of vasoactive molecules showed that cysteinyl leukotrienes, prostacyclin metabolites, and PGE₂ were all increased to a similar degree in both BMPR2^+/– and wild-type mice during 5LO transgene expression, whereas urinary endothelin-1 remained undetectable. Urinary thromboxane A₂ metabolites, in contrast, were significantly higher in BMPR2^+/– than in wild-type mice and paralleled the increase in RVSP. Platelet activation markers, serotonin, and soluble P-selectin showed a trend toward higher concentrations in BMPR2^+/– than wild-type mice. Cell culture studies found that BMP treatment reduced interleukin-1ß–stimulated thromboxane A₂ production in the pulmonary epithelial cell line A549.

Conclusions— BMPR2^+/– mice do not develop pulmonary hypertension spontaneously; however, under inflammatory stress, they are more susceptible to an increase in RVSP, thromboxane A₂ production, and vascular remodeling than wild-type mice.

Key Words: inflammation • hypertension, pulmonary • vasoconstriction • bone morphogenetic proteins • thromboxane

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